Current and Future Treatment of Chronic Hepatitis C

John Scott, MD, MSc University of Washington

Case
43 yo Asian woman w/ chronic Hep C, GT 1, HCV RNA level of 2 million IU/ml ALT 53, INR 1.0, Albumin 4.1 Liver biopsy: grade 2 inflammation, stage 2 fibrosis HTN What to do next?
Treat now or wait?

Outline
Epidemiology Natural History Current Therapy -Efficacy -Side effects -Mechanism of action -Kinetics Future Therapy

Epidemiology
3.9-4.1 million Americans are HCV Ab+
May be as high as 7 million

2.7-3.2 million are chronically infected Highest prevalence in 30-54 yo Highest prevalence in African Americans and Hispanics
CDC. MMWR 1998 47(RR-19):1-38 Alter M. NEJM 1999 341:546-52 Armstrong GL. Ann Intern Med 2006 144:705-14

Risk Factors for HCV

Injection drug use (60%) Blood transfusion before 1992 Multiple sex partners Iatrogenic (hemodialysis, re-use of vials, etc) Intranasal cocaine Piercing, tattooing, scarification Unknown (10%)

Evolution of therapy for HCV

60

Sustained Virologic Response (%)

50

40

30

20

10

0 IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12m PEG 12m PEG/RBV 12 m Therapies and Duration

~1990s

mid-90s

~2000-01

What is Pegylation?
Covalent attachment of polyethelene glycol to peptide Increases hydrodynamic size Prolonged circulation, delayed renal clearance PegIntron (12kd, Schering), Pegasys (40kd, Roche) Enzon pharmaceutical
Adenosine deaminase Others: Neulasta (GCSF), doxorubicin

Side Effects of PegIFN/Ribavirin

Depression ranging

Interferon Man

from mild to suicidality Irritability, aggressive behavior Worsening of mania Fatigue Insomnia Myalgias, fever, flulike symptoms Hair loss Cytopenias
Slide courtesy Chia Wang

The importance of viral kinetics

8 Therapy 7 6

Log (10) HCV RNA

Non-response (NR) 5 Slow response with relapse 4 3 2 1 0 0 1 2 3 4 Time (wks) 12 24 48 72 Early virologic response (EVR) Rapid virologic response (RVR)

Scott J and Gretch DR. JAMA 2007.

Kinetics and SVR

GT 1 (Pegasys + RVN)
Time Wk 4 Wk 12 Neg Neg HCV RNA status <2 log Neg <2 log >2 log Any Any

Wk 24
SVR

Neg
91%

Neg
60%

Neg
43%

Pos
2%

Ferenci P. J Hepatol 2005; 43:425-33

Mechanism of Action: Interferon

HCV
HCV virions Interferon alfa IFN receptors JAK Viral RNA ADA Assembly
HCV replicative complex

OAS: activates antiviral RNAses PKR: inactivates viral ptn translation ADA: edits viral RNA

PKR STAT STAT1 IRF9 OAS

ISG mRNA ISGF3 ISRE

Adapted from Hoofnagle J. NEJM 2006

Effect of IFN-/Ribavirin
Average HCV RNA level reduction (log IU/ml)
+0.5
0.0 -0.5 -1.0

-1.5
-2.0 -2.5 -3.0

-3.5
-4.0 -4.5 -5.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Group A: untreated Group C: IFN-3 MU tiw Group D: IFN-3 MU tiw + ribavirin 1.0-1.2 g qd

Days

(Pawlotsky et al., Gastroenterology 2004;126:703-14) slide courtesy of JM Pawlotsky

Ribavirin Prevention of Relapse

Treatment Follow-up

% relapse (HCV RNA +)

Continue ribavirin > wk 24 Stop ribavirin at wk 24

*
*

* p<0.05

*
24 30

*
60 72

36 48 52 Weeks of treatment

(Bronowicki et al., Gastroenterology 2006;131:1040-8) slide courtesy of JM Pawlotsky

Ribavirins Antiviral Mechanisms

Direct inhibition of HCV RNA-dependent RNA polymerase ? Depletion of intracellular GTP pools via IMPDH inhibition ? RNA mutagenesis leading to "error catastrophe" ?

Ribavirin Antiviral Mechanisms

O H N 2 N O N

HO

?
25OAS PKR Mx ADAR1 ISG20 ISG54 ISG56

HO

OH

Slide courtesy JM Pawlotsky

Future Therapies
Coming soon! (2011?) Potent Rapid antiviral resistance if used by itself More side effects

HCV Life Cycle: Key Features

Multiple proteins mediate HCV entry:
CD81, Scavenger Receptor B1, Claudin 1, Occludin, Very Low Density Lipoprotein Receptor

Input HCV RNA is translated, a polyprotein is formed, and individual viral proteins are released from polyprotein by cellular and viral proteases HCV proteins associate with endoplasmic reticulum membranes, the site of HCV replication Virion assembly occurs at lipid droplets HCV leaves the cell by hitching a ride on the apolipoprotein B secretion pathway HCV life cycle is intimately tied with lipid metabolism
Slide courtesy S Polyak

HCV Variability
RNA virus, RDRP lacks proof-reading function Mutations arise during replication are not corrected
Genotypes
genetically divergent HCV isolates that can be grouped phylogenetically

Quasispecies
Highly related yet genetically distinct viruses

Slide courtesy S Polyak

Drug Development is NOT Easy

-one for every 1,000 drugs makes it into humans -One in 5 receive FDA approval
Slide courtesy S Polyak

HCV Drug Development

Phase of Development Viral entry inhibitors
Hepatitis C immunoglobulin HCIg) HCV-Ab 68 and Ab 65 (monoclonal Ab)

Preclinical

II

III

IV

HCV RNA translation inhibitors

ISIS 14803 (antisense) AVI 4065 (antisense) Heptazyme (ribozyme) VGX-410C (small molecule IRES inhibitor) TT 033 (siRNA)

* *

Posttranslational processing inhibitors

NS3-4A serine proteinase inhibitors BILN 2061 ITMN 191 VX-950 SCH 503034 ACH-806/GS-9132

* * * * *

HCV replication inhibitors

NS5B polymerase inhibitors MK-0608 HCV-796 R1626 JTK-003 NM-283 XTL 2125 Cyclophilin B inhibitors DEBIO-025 NIM 811 NS5A inhibitors A-831, A-689 Helicase inhibitors QU663 Recombinant Ab fragments

Virus assembly and release inhibitors

UT-231B (iminosugar-glucosidase inhibitor) Celgosivir (glucosidase inhibitor)

(Pawlotsky JM, Chevaliez S, McHutchison JG, Gastroenterology 2007;132:1979-98)

HCV Lifecycle

HCV Lifecycle

NS3 Protease Targets

Serine proteinase catalytic site

(Pawlotsky JM, Chevaliez S, McHutchison JG, Gastroenterology 2007;132:1979-98)

NS3 Protease Inhibitors Having Reached Clinical Development

Peptidomimetic inhibitors
BILN 2061 (Boehringer-Ingelheim) Telaprevir (VX950, Vertex & Tibotec) Boceprevir (SCH503034, Schering-Plough) TMC 435350 (Tibotec) ITMN-191 (InterMune) MK-7009 (Merck) BI 201335 (Boehringer-Ingelheim

VX-950 Alone or in Combination with Pegasys: Mean Viral Response

1
HCV RNA Change from Baseline (Log10 IU/mL)

0 -1 -2 -3 -4 -5

Baseline

Pegasys + placebo

VX-950

VX-950 + Peg-IFN

-6 B
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Study Time (In Days)

Reesink H et al. EASL. April 26-30, 2006. Vienna, Austria. Abstract 737.

Slide courtesy Roche Medical Affairs

Phenotypic Characterization of Telaprevir-Resistant Variants

Highly sensitive clonal method Detect 5% frequency of variants Performed at days 4, 8, 12, 14 80 sequences/patient/time point
Wild type T54A V36A/M R155K/T 36/155 A156V/T

Low resistance

High resistance

Adapted from Kieffer T, et al. 2006 AASLD, Boston, #92

Telaprevir 8

Peginterferon + Ribavirin

Log(10) HCV RNA IU/ml

2 LOD = 10 IU/ml 14 Days 100

Telaprevir + Peg/RVN
8 Log(10) HCV RNA IU/ml

Peginterferon + Ribavirin

14 Days

100

Adapted from Kieffer T, et al. 2006 AASLD, Boston, #92

IFN sparing regimens?

Roche: protease + polymerase inhibitor (phase I) Merck/Schering: protease + polymerase inhibitors

Remaining questions
Why doesnt IFN work in some patients? Is IFN necessary if you have two potent antivirals? How many antiviral targets are needed and how long is therapy needed? Target lipid metabolism?

Back to the case

43 yo Asian woman w/ chronic Hep C, GT 1, HCV RNA level of 2 million IU/ml ALT 53, INR 1.0, Albumin 4.1 Liver biopsy: grade 2 inflammation, stage 2 fibrosis HTN What to do next?
Treat now or wait?

Thanks!
Larry Corey, MD

Chia Wang, MD
Dave Gretch, MD, PhD Erica Coppel Erica Seddig Wan Chong Qiu Steve Polyak, PhD Jean Michel Pawlotsky, MD

Patients
NIH/NCRR